rs121434513

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_015488.5(PNKD):c.97G>C(p.Ala33Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000302 in 1,613,830 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A33D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 8 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2O:1

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

PNKD links:

PNKD (HGNC:):

PNKD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218271411-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.028998673).

BP6

Variant 2-218271410-G-C is Benign according to our data. Variant chr2-218271410-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1894.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Benign=2}. Variant chr2-218271410-G-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKD	NM_015488.5 linkuse as main transcript	c.97G>C	p.Ala33Pro	missense_variant	2/10	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415
PNKD	NM_001077399.3 linkuse as main transcript	c.97G>C	p.Ala33Pro	missense_variant	2/3		NP_001070867.1	Q8N490-2
PNKD	XM_017003771.2 linkuse as main transcript	c.97G>C	p.Ala33Pro	missense_variant	2/9		XP_016859260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 linkuse as main transcript	c.97G>C	p.Ala33Pro	missense_variant	2/10	1	NM_015488.5	ENSP00000273077.4		Q8N490-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000601

AC:

151

AN:

251448

Hom.:

AF XY:

0.000920

AC XY:

125

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00467

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000319

AC:

466

AN:

1461584

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

359

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00517

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000145

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1

Pathogenic:1Uncertain:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Apr 14, 2022	This variant has been reported in the literature in 2 individuals: 1 individual with paroxysmal non-kinesigenic dyskinesia and 1 individual with progressive non-paroxysmal chorea and foot dystonia (Ghezzi 2009 PMID:19124534, Pandey 2018 PMID:30174277). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.4% (143/30616) including 3 homozygotes (https://gnomad.broadinstitute.org/variant/2-219136133-G-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:1894). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies suggest that this variant will impact the protein and decrease protein stability (Ghezzi 2009 PMID:19124534, Shen 2011 PMID:21487022). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

PNKD: BS1, BS2 -

Paroxysmal nonkinesigenic dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.029

T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.55

N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.31

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.028

D;T

Polyphen

1.0

D;P

Vest4

0.56

MVP

0.85

MPC

0.49

ClinPred

0.088

GERP RS

3.8

Varity_R

0.25

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over